It has previously been shown that inescapable (IS), but not escapable (ES) shock potentiates the rewarding properties of morphine as measured by conditioned place preference (CPP) and psychomotor activation (PA), and that this potentiation may be mediated by dorsal raphe nucleus (DRN) serotonin (5-HT) neurons. The medial prefrontal cortex (mPFC) has been implicated in both reward and stress, and is a projection region of the DRN. The mPFC also contains dopaminergic afferents from the ventral tegmental area (VTA), which has long been the focus of studies exploring the rewarding properties of drugs. There is evidence to suggest that 5-HT and dopamine (DA) interact in the prefrontal cortex, and that this interaction is mediated via the 5-HT3 receptor. The involvement of PFC monoamines in the IS potentation of morphine reward has not been examined. The specific aims of this proposal are 1) to characterize the effects of stressor controllability on 5-HT sensitization and on morphine induced increases in dopamine (DA) in the medial prefrontal cortex (mPFC) and to determine whether these effects generalize to cocaine, 2) to determine the effects of DRN 5-HT neurons on morphine induced increases in 5-HT and DA in the PFC, morphine conditioned place preference (CPP), and morphine induced psychomotor activation (PA), 3) to determine the role of the PFC 5-HT3 receptor in IS potentiation of induced increases in 5-HT and DA in the PFC, morphine CPP and PA, 4) to determine the necessity of direct action of morphine in the DRN on IS potentiation of morphine induced 5-HT and DA in the PFC, CPP, and PA.